Reaction Steps
To a stirred and ice-cooled suspension of (2R*,3S*,4S*,5S*)-4-benzyloxymethyl-5-hydroxymethyl-3-methoxycarbonyl-2-phenylpyrrolidine semifumarate (12.0 g, 29.0 mmol) in 1M NaOH aqueous solution (70.0 ml, 70.0 mmol) and DME (40 ml) was added benzyl chloroformate (Cbz-Cl, 4.97 ml, d1.195, 34.8 mmol) rapidly. After the heterogeneous white reaction mixture was stirred with ice-cooling for an hour, H2O (40 ml) and AcOEt(40 ml) was added to dissolve the white solids, and then a further amount of Cbz-Cl (1.0 ml, d1.195, 7.0 mmol) was added to the mixture at room temperature; on the addition, the reaction mixture became neutral. After stirring at room temperature for 30 minutes, the reaction went to almost completion. The stirring was continued at room temperature overnight, and then the layers were separated. The aqueous layer was extracted with AcOEt (50 ml×4). The combined organic layer and AcOEt extracts were washed with 0.5M NaOH aq. solution (×2), half sat. NaCl aq. solution (×1), 0.5M HCl aq. solution (×1), sat. NaCl aq. solution (×1), sat. NaHCO3 aq. solution (×1) and sat. NaCl aq. solution (×1), dried (MgSO4), and concentrated in vacuo to give crude title compound (15.9 g, quant.) as an almost colorless viscous oil: IRmax (film): 3420(s), 1738(vs), 1698(vs), 1680(vs), 1605(w), 1595(w), 1492(s), 1280(s), 1210(s), 1075(s), 758(s), 699(vs) cm-1 ; 1H-NMR δ: 7.53-7.10(m, 14H), 6.94(br.s, 1H), 5.30(d, J=9.5 Hz, 1H), 5.02(br.s, 2H), 4.53(d, J=12.1 Hz, 1H), 4.47(d, J=12.1 Hz, 1H), 4.13-3.90(m, 3H), 3.62(dd, J=9.7, 3.5 Hz, 1H), 3.58-3.41(m, 1H), 3.53(dd, J=9.7, 4.6 Hz, 1H), 3.29(s, 3H), 2.73(br.s, 1H), 1.61(br.s, OH, 1H) ppm. This was employed in the next step without further purification.
